A Combined Molecular Docking, Dynamics Simulation, and In Vitro Evaluation of Hydroxythioxanthones as Antidiabetic and Antioxidant Candidates

Abstract

ABSTRACT. This research conducts a comprehensive investigation of hydroxythioxanthone derivatives through an integrated methodology that includes molecular docking, molecular dynamics (MD) simulations, and in vitro evaluations of antidiabetic and antioxidant activities. Molecular docking and MD simulations were performed to elucidate the binding interactions and dynamic stability of these compounds in complex with the α-glucosidase enzyme. The docking results indicated that the hydroxythioxanthone derivatives exhibited binding affinities ranging from −5.48 to −6.42 kcal/mol. In contrast, α-D-glucopyranose and quercetin demonstrated higher binding affinities of −6.99 and −7.01 kcal/mol, respectively. Subsequently, 100 ns MD simulations confirmed the stability of the ligand–protein complexes, as evidenced by consistently low values of root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg). The antidiabetic activity assay revealed that 4-chloro-1-hydroxythioxanthone (TX4) and 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) exhibited strong inhibitory effects against α-glucosidase, with IC₅₀ values of 78.35 and 91.97 µg/mL, respectively, whereas quercetin showed a lower IC₅₀ value of 1.25 µg/mL. Furthermore, the antioxidant evaluation demonstrated that 2-chloro-1-hydroxythioxanthone (TX3) and 4-chloro-1-hydroxythioxanthone (TX4) possessed IC₅₀ values of 87.48 and 17.72 µg/mL, respectively, while ascorbic acid served as the reference compound with an IC₅₀ value of 9.15 µg/mL. Keywords: antidiabetic, antioxidant, molecular docking, molecular dynamics, thioxanthone